The relatively large meal sizes consumed by sit-and-wait-foraging snake species make them favorable for investigating specific dynamic action, the rise in metabolic rate associated with digestion. Hence, we measured O2 consumption rates (VO2) before and up to 20 d after Burmese pythons (Python molurus) either had only constricted and killed rodent meals or had also been allowed to consume meals ranging in size from 5% to 111% of their body mass. Postprandial VO2 peaked within 2 d at a value that increased with meal size, up to 44 times standard metabolic rate for the largest meals. In addition to being the largest known magnitude of postprandial metabolic response, this also exceeds the factorial increase in VO2 during peak physical activity for all studied animals except perhaps racehorses. Specific dynamic action, calculated from the extra VO2 above standard metabolic rate over the duration of digestion, increased with meal size and equaled 32% of ingested meal energy. The allometric exponent for body mass was 0.68 for standard metabolic rate, 0.90 for peak postprandial VO2, and 1.01 for specific dynamic action. Specific dynamic action is higher, and standard metabolic rate is lower, in sit-and-wait-foraging snake species than in actively foraging snake species. This suggests that sit-and-wait-foraging snakes, which consume large meals at long and unpredictable intervals, reduce standard metabolic rate by allowing the energetically expensive small intestine and other associated organs to atrophy between meals but thereby incur a large specific dynamic action while rebuilding those organs upon feeding.